Our Center is dedicated to resolving the role of inherited abnormalities in mitochondrial DNA in Parkinson's Disease (PD). PD is the second most prevalent neurodegenerative disorder of adults and afflicts about 1 million Americans. Life expectancy is shortened and quality of life is adversely affected by PD. While rare families with mutations in synuclein proteins have been described,, the cause of PD in the vast majority of cases is unknown. Traditional Mendelian genetic factors do not appear to contribute prominently to etiology. Furthermore, currently identified environmental risk factors also appear to play a minimal role in influencing the risk of developing PD. Investigators in our Center first articulated the hypothesis that inherited mitochondrial DNA abnormalities might play a pathogenic role in PD and account for its sporadic appearance. They were first to demonstrate a mitochondrial Complex I synthetic defect in PD. They were the first to adapt the mitochondrial transgenic cytoplasmic hybrid ("cybrid") technique to replicating neural cells and to use cybrid technology to demonstrate that the complex I synthetic defect in PD occurred as a consequence of abnormalities in mitochondrial DNA. Our group was the first to demonstrate that an inherited mutation in mitochondrial DNA (mtDNA) could contribute to PD in a multi-generational family with exclusively matrilineal transmission, and the first to provide evidence of a predominance of maternal transmission in PD. Investigators in our Center were the first to show that PD mitochondria in cybrids produced abnormalities in intracellular calcium signaling, increased oxidative stress, depressed mitochondrial membrane potential, increased NFkappaB gene activation and altered mitochondrial movement and morphology. These important biological consequences for cell function and survival may represent mechanisms of how PD mtDNA mutations increase risk of neuronal death in PD. This track record of scientific progress, coupled with the knowledge that inherited abnormalities of mitochondrial DNA constitute a plausible etiology for most cases of PD, underscore the significance of the proposals in this application. In the four Projects in this application we will sequence mitochondrial DNA in subjects with PD, characterize abnormalities of mitochondrial structure and function in PD, clarify the genetic epidemiology of PD, and elucidate the relationship between mitochondrial dysfunction and neuronal death. Results of these studies may lead to preclinical diagnostic procedures and specific therapies to halt neuronal death in PD.